The goal of this Funding Opportunity Announcement (FOA) is
to provide support for investigators to develop new drugs for the prevention
or treatment of Alzheimer’s disease (AD). Specifically, this initiative is
aimed at researchers who have promising small molecule compounds but lack
outside drug development expertise and infrastructure support to advance
these compounds to the clinic. This Alzheimer’s Disease Therapeutics Program
adjunct to the NIH Blueprint Neurotherapeutics Program will allow
investigators access to a “virtual pharma” network of contract research
organizations, technical and regulatory experts and project managers, with
extensive biopharma-industry experience. The long-term goal of the
Alzheimer’s Disease Therapeutics Program is to advance projects from
medicinal chemistry optimization through Phase l clinical trials and
facilitate industry partnership for their further development.

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide, except where instructed to do otherwise
(in this FOA or in a Notice from the NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA)
is required and strictly enforced. Applicants must read and follow all
application instructions in the Application Guide as well as any
program-specific instructions noted in Section
IV. When the program-specific instructions deviate from those in the
Application Guide, follow the program-specific instructions. Applications that
do not comply with these instructions may be delayed or not accepted for review.

Alzheimer’s disease (AD) is one of the most common
age-associated diseases, and because of the aging of populations worldwide this
disorder is predicted to reach epidemic proportions, with an enormous human and
economic burden by the year 2050. To avert this public health crisis effective
therapies that prevent AD, slow its progression or treat its cognitive and
behavioral symptoms are urgently needed. There are currently no therapies that
meet this need.

Over the past three decades significant progress has been
made in understanding the neurobiology of AD. Notwithstanding these advances
the development of effective AD therapies has been challenging, as is evidenced
by the recent string of disappointing clinical trials. This has led to the
perception that the biopharmaceutical industry is not properly developing AD
therapies. Many factors contribute to the lack of progress in developing an
effective AD therapy including: the complexity of the disease, the lack of
animal models that accurately recapitulate the disease, the paucity of well
validated biomarkers that correlate pathophysiology with clinical disease
stages, and the strong possibility that AD drug candidates have failed in the
clinic because they are designed to ameliorate a pathology that is already too
advanced at the time patients are treated. In addition to scientific factors,
there are legal, regulatory and new economic factors that have hindered the development
of AD therapies and have created the so-called “Valley of Death”.

As a consequence of the failure to translate scientific
advances and increased R&D expenditures into new drug approvals, there is
the increased threat that the biopharma industry will re-strategize and pull
out of the AD field entirely, leaving little hope for millions of people with
the disease and their families. To address the unmet needs of millions of AD
patients and to catalyze AD drug development, the NIH Blueprint for Neurosciences
has created, with this FOA, an adjunct Blueprint AD Therapeutics Program.

B. Overview and Objectives

To expand and support AD drug discovery by the neuroscience
community, the NIH Blueprint for Neuroscience Research is establishing the AD
Therapeutics Program. This new program will utilize the ‘virtual-pharma’
network of contract service providers and consultants established by the NIH
Blueprint for Neuroscience Research-Grand Challenge for Neurotherapeutics. The
types of contract research organization (CRO) support provided on an in-kind
basis will be for: medicinal chemistry optimization, Absorption, Distribution,
Metabolism, Excretion and Toxicology (ADMET), Investigational New Drug (IND)
enabling safety-toxicology, and Phase l clinical trial.

This Funding Opportunity Announcement (FOA) is soliciting
applications for U01 cooperative agreement awards from investigators with small
molecule compounds that could be developed into clinical candidates within this
network. Awarded researchers will, in collaboration with the Blueprint
consultants and NIH staff, design and implement a drug development strategy
through clinical Phase l.

Applications will be considered from investigators with
small molecules, that are at either of two stages of the drug discovery
process: 1) hit-lead stage compounds that require iterative medicinal chemistry
optimization to improve potency, pharmacological and chemical/physical
properties, ADMET, IND-enabling safety-toxicology and Phase l clinical studies;
2) IND candidate- stage compounds that require IND-enabling preclinical
clinical studies and subsequent Phase l clinical studies. The long-term goal of
this program is to advance a pipeline of drug candidates through technical and
feasibility milestones to produce at least one novel AD drug that successfully
completes Phase l trials.

To be accepted into the network at the hit-lead entry point,
applicants to this FOA must have in hand the starting compounds for chemical
optimization and bioactivity assays for testing new analog compounds generated
through the virtual-pharma network (see Entry Criteria below for more details).

To be accepted at the IND-candidate entry-point applicants
must have the compound in hand and must provide the following information: a
target product profile, medicinal chemistry optimization performed to date
including identified liabilities, evaluation of pharmacokinetics (PK) and
pharmacodynamics , evaluation of ADMET properties including products of
metabolism, microsome stability and CYP profile, in vivo efficacy evaluation,
including dosing (see Entry Criteria below for more details).

Successful applicants under this FOA will receive 1) funding
for biological assessment of compounds in their laboratories, 2) access, at no
cost, to drug development resources that typically reside in the pharmaceutical
industry, including iterative medicinal chemistry optimization,
pharmacokinetics, toxicology, manufacture and formulation services, and Phase I
clinical safety testing and 3) strategic guidance from experienced drug
discovery consultants identified by NIH. The budget of the U01 application will
support only the work in the investigators’ laboratories.

Each drug discovery project will be directed by a
collaborative Lead Development Team, co-chaired by the U01 Program Director/Principal
Investigator (PD/PI) and a consultant with extensive industry expertise
identified and supported by the NIH Blueprint for Neuroscience Research. The
team will also include consultants with additional expertise supported by NIH,
and NIH staff. Work will be guided by this team with oversight from the
Blueprint Neurotherapeutics Steering Committee and, ultimately, the NIH
Blueprint for Neuroscience Research Institute and Center Directors.

This NIH program is structured to allow the PDs/PIs’
institutions to retain ownership of intellectual property for compounds
developed within the network. The PIs' institutions therefore fully retain the
responsibility for the ultimate commercialization of compounds developed through
this effort.

C. Entry Criteria

Applicants seeking support through this program must have
available small-molecule compounds that are considered high quality from a
druggability perspective, with validated biology relevant to the
pathophysiology of AD.

For entry at the hit-lead stage, compounds must have the
potential for optimization through iterative medicinal chemistry. In addition,
hit-lead stage projects, applicants must have the capabilities and resources to
conduct the bioactivity and efficacy testing including validated cellular or animal
efficacy models to assess compounds synthesized in the development process.

The minimal entry criteria for IND- candidate stage projects
is a high quality Developmental Candidate (defined below). The entry criteria
for the Blueprint AD Therapeutics Program are detailed below.

1. Biological Rationale

Hit-lead and IND-candidate compounds entering the
program must be well-supported by biological rationale data that is
sufficiently compelling and rigorous to justify the entry into the program.
Applicants should include a brief statement of the therapeutic hypothesis in a
Projected Product Profile that includes: the projected patient reduction of
symptoms, slowing disease progression, side effects, dose administration and
regimen, and sustainability of effect.

While it is not necessary to know the precise
molecular target of the compound, the applicant should briefly summarize what
is known about the compound’s mechanism of action and whether the compound
engages a disease-relevant pathophysiological mechanism.

For compounds with known targets, the applicant
should summarize the evidence that validates the drug target from cellular or
animal models and clinical studies, provide a brief summary of the rationale
for the selection of the target, the level of agreement in the field regarding
the target’s role in disease pathogenesis and clinical relevance of the target,
including the optimal disease stage (asymptomatic, mild cognitive impairment
(MCI), mild, moderate or severe AD) to pharmacologically engage the target.

Applicants proposing to develop multi-target
compounds should summarize the cumulative pathogenic pathways that the drug is
proposed to engage and provide a strong clinically-relevant rationale for this
approach. In addition, describe the small molecule (see below), its impact on
the target, and the rationale for selecting the compound over similar entities
(if they exist).

Applicants should discuss the disease-relevance of in
vitro or in vivo models that are proposed or that have been used and whether
the endpoints measured and levels of activity observed are likely to be
clinically relevant. In addition, applicants should discuss plans to incorporate
any translatable, clinically-relevant biomarkers into their preclinical
development program.

Compounds entering the Blueprint AD Therapeutics
program at this stage of development must provide information in the following
areas:

1) Compound structure: The compound or hit series must be of a size and molecular structure that can
be readily synthesized and chemically modified;

2) Activity in primary and
secondary/confirmatory assay(s): For biochemical assays, compounds
generally should show activity at 1µM or below. For cell-based assays, an IC50
or EC50 of <10µM is desirable:

3) Determination of identity and
purity: The starting compound(s) should have proof of identity and
purity (typically >95%, as determined by, e.g., NMR, melting point, or
LC/MS, with no single impurity > 0.5%);

4) Compound target selectivity: In cases where the molecular target of compound action is known, the applicant
should demonstrate the degree of selectivity for the intended target over
closely related targets. Preliminary counter-screening to determine selectivity
across a broad panel of unrelated pharmacological targets (e.g., G
protein-coupled receptors, kinases, etc.) is strongly encouraged;

6) Structure-activity relationship
(SAR): Demonstration that chemical analogs of a proposed compound
show similar biological activity is required. SAR information may have been
derived from activity of analogs in a screening library or from testing of commercially
available analogs;

7) Intellectual property:
Applicants should provide information on patents retained or filed on the
compound as well as license rights to use the compound.

IND-candidate
compounds

Compounds entering this stage should be considered
Development Candidates (optimized lead compounds). Applicants proposing the
development of IND-candidate compounds should provide a brief summary of the
current state of the project including description of medicinal chemistry
performed to date, remaining liabilities and potential for further
optimization; ADMET properties, efficacy in an accepted animal model; any known
or suspected drug liabilities or challenges related to their drug candidate.

Applicants proposing development of IND-candidate
compounds should provide information on the following areas:

1) Target Product Profile (TPP): provide a brief statement of the overall intent of the drug development program
that lists the specific studies completed. The TPP should include the
following: drug indication and usage, use in specific patient population,
delivery mode, treatment duration, regimen, efficacy;

7) Intellectual Property:
describe IP on the compound. The applicant should include a list of any
patents issued or pending with respect to the compound or to any
non-commercially available technology/material required for the development of
the compound;

8) Competitive landscape:
briefly describe the competitive landscape for the therapeutic approach
including the target and comparable compounds (if they exist).

3. Proposed Assays

This initiative is not intended to support
development of new bioactivity assays, thus the applicant must have in hand
well-characterized assays and models. Applicants should have three types of
assays that can form the basis of a bioactivity testing funnel: 1) a moderate
throughput primary screening assay, 2) one or more secondary assays for
confirmation of activity and potential efficacy and 3) counter screening assays
for target selectivity, where necessary. The testing funnel must include at
least one cell-based assay. For each type of assay, the parameters that should
be discussed in the application are outlined below.

Primary
screening assay. This must be an assay with moderate throughput or
better, e.g., a reporter assay, which will be used to perform routine weekly
screening of compounds synthesized for iterative medicinal chemistry. To inform
the medicinal chemistry design, the assay must be sufficiently robust and
reproducible to reliably rank compounds with similar activities. The primary
screening assay should meet the following criteria:

A statistical
demonstration of reliability, e.g., a Z’ score =0.5 and a coefficient of
variation (CV) =20%

A
reproducible demonstration of dose-response over at least 3 orders of magnitude
(e.g., 0.1-10µM) with a positive control compound.

Throughput
of at least 20 compounds per 1-2 weeks, run with sufficient replicates to
produce robust and reproducible 10-point dose-response curves.

Secondary
confirmation assays. The applicant must have one or more secondary
assays with sufficient biological validation and reproducibility to confirm the
activity of compounds identified in the primary assay and demonstrate potential
efficacy in the target disorder. These may be low to moderate throughput
assays. Ideally, at least one secondary assay would be capable of generating
dose-response data for multiple compounds simultaneously.

Selectivity
and counter-screening assays. Where the molecular target of drug
action is known, e.g., a particular kinase, it may bear similarity to other
cellular targets. In these cases, the applicant should describe criteria
for compound specificity for these targets and propose a strategy for using
screening assays to determine that specificity. Where aspects of the screening
approach are prone to unwanted activities or artifact, or mechanism-based or
compound-based side effects are anticipated, counter screens should be proposed
to rule out these unwanted activities. Proposed counter-screening and
selectivity assays should have demonstrated reliability and adequate throughput
for their proposed use in the development program

D. Projects Not Responsive to this Announcement

Small molecule compounds that have already completed IND-enabling
studies.

Projects that propose to develop generic or off-patent compounds
for AD.

Projects that propose to repurpose, or develop new formulations
or drug delivery systems for compounds that have previously been approved for
another indication by FDA or any other worldwide regulatory agency.

Research aims appropriate for an investigator-initiated R01
grant, such as understanding underlying biological mechanisms of disease,
should not be included in an application under this FOA.

E. Timeline of Drug Development and the U01
Investigator’s Role

Directing compounds through the drug development pipeline
will be a collaborative effort. After award, a Lead Development Team (LDT) will
be formed to collaboratively manage and coordinate the progress of compounds
through the development pipeline. The team will be co-chaired by the U01
investigator and a drug development consultant identified and supported by the
Blueprint Neurotherapeutics program. The team will include other consultants as
needed at each stage of the project to advise on chemistry, biology and ADMET
study design and interpretation. The first responsibility of the Lead
Development Team will be to establish a drug development plan involving the
Blueprint Neurotherapeutics Network contractors. This plan will define
activities and advancement criteria for a series of stages through which
compounds will progress during development.

This section outlines the stages and timeline for
development of a hit-lead compound (activities 1-4) and IND-candidate compound
(activities 3 and 4). This section also outlines the roles of the NIH Blueprint
Neurotherapeutics Network and the U01 investigator in each stage of the
pipeline.

1.
Exploratory chemistry/feasibility (for budget purposes, assume 6 months).
Each project will undergo a feasibility phase in which investigators will
validate their primary screening assays for SAR studies and test a collection
of approximately 50-100 chemical compound analogs. These will be supplied to
the investigator by NIH Blueprint Neurotherapeutics contractors. Work in this
phase will be directed toward determining whether the compounds and assays are
amenable to medicinal chemistry optimization. If ADMET properties of the parent
compound have not been characterized at the time of submission, preliminary
studies of PK and toxicological properties also will be conducted during this
phase.

2.
Medicinal chemistry optimization (for budget purposes, assume 2 years).
If the outcomes of the feasibility studies are successful, compounds will enter
a full-scale, iterative medicinal chemistry optimization phase to improve
bioactivity, potency and pharmacological properties. This process of
understanding the structure activity relationship (SAR) between the compounds
and the desired drug properties typically requires dozens of rounds of compound
synthesis and testing. The ultimate goal of the SAR effort is selection of a
pre-clinical candidate compound with sufficient bioactivity and drug-likeness
to proceed to IND-directed pre-clinical safety assessment.

The major role of the U01-funded investigator in this
process is to conduct primary biological assessment of compounds on a regular,
one-to-two week schedule to inform the design of subsequent iterations of
compound synthesis. In addition to a regular testing schedule in the primary
assay, the PD/PI will provide confirmation of the activity of select compounds
in secondary assays and possibly animal models relevant to the drug target.

NIH Blueprint Neurotherapeutics contractors will
produce compound analogs for SAR testing and provide standard screening
services to assess in vitro and in vivo ADMET characteristics of the compounds.

In the first year, medicinal chemistry will be in a
‘hit-to-lead’ phase, focusing heavily on optimizing activity and potency of
compounds in the primary and secondary disease assays. In the subsequent ‘lead
optimization’ phase, SAR will increase emphasis on ADMET properties of the
compounds, with continued monitoring and optimization of bioactivity. If
compound testing in in vivo animal models is proposed, this should be limited
to testing a small number of selected advanced compound analogs (e.g., 3) in
year 3.

3.
IND-enabling studies (for budget purposes, assume 1.5 years).
If a therapeutic candidate is identified which meets the target criteria for
activity, efficacy, and favorable physicochemical and ADMET properties, it will
move into IND-directed pharmacology and toxicology studies. Blueprint
Neurotherapeutics contractors, with direction from the Lead Development Team,
will conduct the preclinical safety studies, GMP synthesis, formulation and
other activities required to ready a compound for human testing.
Blueprint Neurotherapeutics contractors will provide data and reports in
a format suitable for inclusion in an IND application and will assist in the
development of the application. The U01 investigator will be responsible for the
submission of the IND application and scheduling meetings with the FDA.

4.
Phase I clinical trial (for budget purposes, assume 1 year).
Once an IND has been submitted successfully to the FDA, a Phase I clinical
trial, typically in healthy volunteer subjects, will be conducted by a
Blueprint Neurotherapeutics contractor. The development of the protocol and
conduct of the trial will involve input from a Clinical Development Team, which
will include the U01 investigator, clinical consultants identified by the NIH,
and Blueprint Neurotherapeutics staff. Costs associated with the conduct of
clinical trials will be supported outside the U01 and should not be included in
the requested budget. In most cases, Phase I human studies will be conducted
under a contract in the NIH Blueprint Neurotherapeutics Network No human
studies should be included in the direct costs requested in the application..

F. Milestones

Because drug development is an inherently high-risk process,
it is anticipated that there will be a significant attrition rate as projects
move through the pipeline. Go/No-Go milestones will be agreed upon at the start
of each project and, in consultation with the Lead Development Team,
investigators will produce milestone progress reports for independent evaluation
by the Blueprint Neurotherapeutics Steering Committee. Please note that
milestones do not need to be proposed in the application. If a funded project
does not make sufficient progress toward the agreed upon milestones at any
stage, funding for the project and access to Blueprint Neurotherapeutics
contract resources may be discontinued unless an additional source of funding
is identified

G. Intellectual Property

The ultimate goal of the Blueprint AD Therapeutics Program
is to bring new AD drugs to the market. Therefore, the creation and protection
of biotechnology and pharmaceutical industry standard intellectual property
(IP) are significant considerations in designing research strategies and
prioritizing projects for funding. The NIH allows the U01 awardee institution
to gain and maintain assignment of intellectual property rights until the
awardee institution licenses or transfers the IP to another institution. The
awardee institution will maintain full responsibility for funding and managing the
patents of the project as it advances, and will exclusively control the patent
prosecution and licensing negotiations.

The intellectual property position of each drug project will
be evaluated at multiple points throughout the program. The awardee will
be expected to provide written reports to the NIH on the patent program as it
progresses. Failure to build a standard patent estate world-wide may be a
reason for project termination by the NIH. Each U01 application is expected to
address intellectual property issues related to the proposed compounds and
assays, including any infringement of other third party patents, with input
from the institution's technology transfer. Peer reviewers will be instructed
to comment on the intellectual property landscape for each U01 application, and
the NIH may assess the feasibility of developing chemical analogs with a strong
intellectual property position prior to making U01 awards. This evaluation may
include patent searches on chemical structures similar to that of the proposed
parent compound. The project milestone plan will include commercialization
milestones to protect and leverage intellectual property developed through the
Network. The U01 awardee institution will be encouraged to identify potential
licensing and commercialization partners early in the drug development process.
The PD/PI will be encouraged to work closely with technology transfer officials
at his or her institution to ensure that royalty agreements, patent filings,
and all other necessary intellectual property arrangements are completed in a
timely manner.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there
will be substantial Federal scientific or programmatic involvement.
Substantial involvement means that, after award, NIH scientific or program
staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New
The OER
Glossary and the SF 424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

NIH intends to commit up to a total of $1 million for FY
2013; to fund up to 5 awards in FY 2013. In addition, in FY 2013 NIH intends
to commit up to a total of $3M in in-kind drug development services. Awards
issued under this FOA are contingent upon the availability of funds and the
submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are limited and need to reflect the
actual needs of the proposed project. For hit-lead stage projects applicants
are encouraged to keep direct costs to no more than $125,000 per year for the
in vitro bioactivity screening in the early years of the project.

For IND-candidate projects applicants are encouraged to
keep direct costs to no more than $50,000 per year for time/effort in
participating in Lead Development Team activities and attending semi-annual
Steering Committee meetings. (see Section VI.2)

Award Project Period

For hit-lead stage projects the duration of the award can
be up to five years. For IND-candidate projects duration of the award can be
up to two years.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the
applications submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.

System for Award Management (SAM) – must maintain an active entity registration (formerly CCR
registration), to be renewed at least annually. Use the SAM.gov “Manage Entity”
function to manage your entity registrations. See the Grants Registration User
Guide at SAM.gov for additional information.

All Program Directors/Principal Investigators (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director/Principal
Investigator (PD/PI) is invited to work with his/her organization to develop an
application for support. Individuals from underrepresented racial and ethnic
groups as well as individuals with disabilities are always encouraged to apply
for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the
same as one already reviewed within the past thirty-seven months (as described
in the NIH
Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application
Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

SF424(R&R) Other Project Information Component

Facilities
& Other Resources

Applicants should use this section to describe Intellectual
property management and commercialization. Applicants should describe their
institutions’ existing or planned infrastructure for bringing the compounds to
practical application (e.g., licensing for further drug development, managing
intellectual property, commercializing discoveries) consistent with achieving
the program goals. For a multiple-PD/PI, multiple-institution
application, applicants should describe the infrastructure of each institution
for bringing the technologies to practical application and for coordinating
these efforts (e.g., licensing, managing intellectual property) among the
institutions consistent with achieving the goals of the program. Applicants
should clarify how intellectual property will be shared or otherwise managed if
there are multiple PD(s)/PI(s) and institutions involved in the U01-supported
work.

R&R Budget Component

For hit-lead stage programs the U01 award is intended to
support the disease-focused biology studies proposed by the Program
Director(s)/Principal investigator(s) (PD(s)/PI(s)). This includes work done in
the PD(s)/PI(s) laboratory, such as assaying compounds through the screening
assays detailed in the application. For IND-candidate stage programs the U01
is intended to support the PD/PI and Co-PI/consultants for time/effort involved
in participating in Lead Development Team (LDT) activities during the time of
the award. The time/effort requested for LDT activities should not exceed 10%
of the PI(s)/PD(s) or Co-PI(S) total time/effort. For both hit-lead and
IND-candidate projects the U01 budget may include one or two trips per year,
for PI(s)/PD(s)/Co-PI(s), to attend meetings of the Blueprint Neurotherapeutics
Network Steering Committee.

The U01 budget may not support drug development activities
that will be conducted through Blueprint Neurotherapeutics contracts (e.g.,
chemistry, pharmacology, toxicology, regulatory activities and clinical
testing). Equipment requests are allowed but not encouraged. Equipment requests
should be considered only if the equipment is absolutely necessary to the
success of the project and cannot be supported by any other means. This is
likely to be a subject of negotiation before an award is made.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Specific
Aims

For hit-lead stage projects the Specific Aims section
should focus on the goals of medicinal chemistry optimization and the
biological work to be conducted under the U01 grant. For IND-candidate projects
the Specific Aims should focus on specific pre-IND activities that are needed
to advance the compound to IND status and aims of the Phase 1 trial (safety,
dosage- range).

Research
Strategy

Within this section, the following subsections should
be included:

Clinical
Impact and Feasibility: Applicants should include a brief statement of the
therapeutic hypothesis that includes: the projected patient reduction of
symptoms, slowing disease progression, side effects, dose administration and
regimen, and sustainability of effect.

Discuss
how the drug would be an improvement over the current standard of care.
Indicate target clinical population and specific stage of disease in which the
treatment would be most efficacious. Describe possible clinical endpoints and
whether these are accepted by regulatory agencies. Indicate if biomarkers are
available in animal models and humans to detect if the drug engages the target.

Compounds
Proposed for Development: identify the compound and its known properties and
activities; for specific instructions for compounds entering at the hit-lead
or IND-candidate stage see Entry Criteria

Intellectual
Property:Applicants
are encouraged to prepare this section of the U01 application in consultation
with their institutions' technology transfer officials. The applicant should provide
the following information relating to intellectual property: List any
patents issued or pending with respect to the compound, and provide
information on the available patent life; describe any constraints of which
they are aware that could impede the development of analogs of their starting
compounds (e.g., certain restrictions under transfer or sharing agreements,
applicants' previous or present intellectual property filings and publications,
compounds with similar structures that are under patent and/or on the market,
etc.) and how these issues could be addressed; describe any constraints of
which they are aware that would impede use of the assays and models for
research purposes and/or commercial development.

Management
Plan: Describe the roles and extent of participation of key personnel over the
course of the small molecule development process. For hit-lead stage projects-
from compound optimization through Phase I clinical trials; for IND- candidate
projects- from IND enabling studies through Phase I trials. Indicate the
willingness of the PD/PI and key personnel to operate under the cooperative
agreement terms and conditions outlined in section VI.2 of this FOA. If needed,
describe the availability of a clinical consultant with expertise in the target
disorder. Clinical experts should be sought as needed to develop the
application and available after award to aid in determining the goals of the
drug development program and to consult on the design of the clinical
trial.

Resource Sharing Plan

Individuals are required to comply with the instructions
for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and
Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R)
Application Guide, with the following modification:

Generally, Resource Sharing Plans (Data Sharing Plan, Sharing
Model Organisms, and GWAS Sharing Plan) are expected, but they are not
applicable for this FOA.

Appendix

Do not use the Appendix to
circumvent page limits. Follow all instructions for the Appendix as described
in the SF424 (R&R) Application Guide.

Foreign Institutions

Foreign (non-US) institutions must follow policies described
in the NIH
Grants Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in
advance of the deadline to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure accurate
and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD/PI Commons ID in the credential field will prevent the
successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA Commons
and for System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application
Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations,
NIH. Applications that are incomplete and/or nonresponsive will not be
reviewed.

In order to expedite review, applicants are requested to
notify the NINDS Referral Office by email at nindsreview.nih.gov@mail.nih.gov when the
application has been submitted. Please include the FOA number and title, PD/PI
name, and title of the application.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115,
with the following modifications:

Late-breaking research findings will be allowed

The page limit for post-submission materials is 2 printed pages

Concurrence from the Authorized Organization Representative
(AOR) of the applicant organization is required.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

For this particular announcement, note the following:

The market size for the proposed drug will not be considered in
assessing the significance of a project.

Evaluation of the approach should focus primarily on the
rationale and strengths/weaknesses of proposed bioactivity studies and compound
"druggability," since all other drug discovery work (e.g., medicinal
chemistry, PK/tox, phase I clinical testing) will be designed and implemented
by NIH-provided consultants and contractors after award.

Milestones will be developed after award, in collaboration with
NIH-provided consultants. Applicants are not expected to propose milestones. If
milestones are included in the application, reviewers may comment on them, but
milestones may not be considered in scoring the application.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in consideration
of the following review criteria and additional review criteria (as applicable
for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?In particular, how would achievement of the
goals laid out in the Summary of Key Drug Characteristics affect clinical
practice for the proposed disease indication?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD/PI, do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?Recognizing
that the NIH does not require the applicant to have drug discovery expertise,
is the experience with biological testing sufficient to support and inform a
drug discovery effort? Is there sufficient clinical expertise to define the
goals of the drug development effort for the intended disease indication?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed? Is the drug target
or therapeutic strategy sufficiently different from ongoing drug development
programs in industry and academia? Would the proposed drug be expected to give
significantly better clinical outcomes than have been observed for previously
developed drugs with similar structures or targets?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?

Based on the evidence provided, is it reasonable to
believe that a drug that meets the proposed advancement criteria for each of
the proposed bioactivity assays could achieve the desired clinical outcomes
described in the Summary of Key Drug Characteristics? In other words, is there
a strong biological rationale for the choice of drug target, disease models,
and assay design? Do the proposed compound(s) and bioactivity assays meet the
entry requirements for the Blueprint Neurotherapeutics Network?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Intellectual Property

Reviewers may comment on the intellectual property
landscape for the project and note any intellectual property constraints that
potentially could impede drug development and/or commercialization.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NINDS, in
accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact/priority
score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in
response to this FOA.

Applications will be assigned to the appropriate NIH
Institute or Center. Applications will compete for available funds with all
other recommended applications submitted in response to this FOA. Following
initial peer review, recommended applications will receive a second level of
review by the NIH Blueprint Institutes contributing the funds for these awards.
The following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

Feasibility of developing a strong intellectual property position
for compound analogs consistent with achieving the goals of the program.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume
direction, prime responsibility, or a dominant role in the activities.
Consistent with this concept, the dominant role and prime responsibility
resides with the awardees for the project as a whole, although specific tasks
and activities may be shared among the awardees and the NIH as defined below.

The
PD(s)/PI(s) will have the primary responsibility for:

Determining experimental approaches, designing protocols,
conducting experiments, and analyzing and interpreting research data related to
the compound bioactivity testing funded through this U01. (Applicable only to
hit-lead stage projects).

Serving as Co-chair of the Project Lead Development Team (LDT),
presenting project updates in biweekly conference calls and annual face-to-face
meetings of the BPN Steering Committee in the Washington, DC area.

With the LDT, assisting in the development of a project milestone
plan at the outset of the project.

Coordinating and participating with NIH staff and NIH-contracted
consultants in all aspects of scientific and technical management of the
project.

Collaborating and communicating effectively with NIH service
contractors to achieve project goals.

Providing goals and strategies for assay validation, screening
throughput, and quality control, to the NIH Program Official as requested. (Applicable
only to hit-lead stage projects).

Ensuring that primary and secondary screening data and assay
protocols developed as a part of this project are deposited in a centralized
Blueprint Neurotherapeutics (BPN) database according to the timeline agreed
upon by the LDT and the NIH Program Official and according to BPN policies. (Applicable
only to hit-lead stage projects).

Adhering to BPN policies, including those regarding data release,
intellectual property, and publications.

Implementing all scientific and policy decisions approved by the
LDT and the BPN program.

Submitting periodic milestone progress reports in a standard
format, as agreed upon by the LDT and BPN program.

Preparing for annual administrative site visits by NIH staff and
consultants.

Working closely with his/her institution's technology transfer
officials to ensure that royalty agreements, patent filings, and all other
necessary intellectual property arrangements are completed in a timely manner

Awardees will retain custody of and have primary rights to
the data and software developed under these awards, subject to Government
rights of access consistent with current DHHS, PHS, and NIH policies.

NIH
staff has substantial programmatic involvement that is above and beyond the
normal stewardship role in awards, as described below:

With the LDT, assisting in the development of a project milestone
plan at the outset of the project.

Providing a perspective on the priorities of the NIH Blueprint
for Neuroscience Research and BPN.

Facilitating collaboration among the awardee, NIH-contracted
consultants, and service providers.

Enhancing the project progress by providing access to various NIH
resources when appropriate.

Providing technical assistance, advice, and coordination to the
project, although the dominant role and responsibilities for the activities
funded by the U01 resides with the awardee.

Coordinating testing of compounds under BPN contracts.

Providing data from the BPN contractors to the LDT and project
PD/PI.

Coordinating reports and presentations of project progress to the
BPN Steering Committee.

Serving as scientific liaison among the awardee, other NIH
program staff, and the BPN Project Team (the committee of NIH staff that
manages the BPN).

Reporting periodically on the progress of the project to the BPN
Project Team.

The NIH Blueprint Directors Committee (the Directors of the
Institutes and Centers that comprise the Blueprint) will make decisions on
project continuation based on Steering Committee recommendations, portfolio
balance, and budget considerations.

Additionally, an agency program official or IC program director
will be responsible for the normal scientific and programmatic stewardship of
the award and will be named in the award notice.

Areas
of Joint Responsibility include:

Project Lead Development Team (LDT): The LDT will be
co-chaired by the PD/PI and an NIH-contracted drug development consultant and
will include additional members from the PD/PI’s group, consultants and NIH
staff. This team will collaboratively set strategic direction and guide the
work flow for the project on an ongoing basis. The LDT will meet every two weeks
via teleconference to analyze and interpret data from the PD/PI and contracted
laboratories and to formulate the subsequent experimental plan. The team will
produce progress reports for evaluation by the BPN Steering Committee and BPN
Project Team as needed.

BPN Steering Committee: The Steering Committee will be
responsible for reviewing and evaluating the progress of the BPN projects in
meeting their milestones and goals, and making recommendations about individual
projects to the BPN Project Team and the NIH Blueprint Directors Committee (the
Directors of the Institutes and Centers that comprise the Blueprint). The
Steering Committee will be composed of 6-8 senior non-federal scientists who
are not directly involved in the activities of the BPN. The NIH Blueprint
Directors will appoint members to the Steering Committee. The BPN Program
Officers, Project Scientists and BPN Project Team members may attend the
Steering Committee meetings as non-voting participants.

The BPN Steering Committee will have the following
involvement:

The BPN Steering Committee will meet in person at least once a
year and by conference call quarterly. During part of the face-to-face
meetings, there will be individual meetings with the project PD/PIs for
presenting project progress and outcomes

The Steering Committee will review progress of the individual
projects and make recommendations for improving project performance.

Based on progress of individual projects, the Steering Committee
will assess whether sufficient progress is being made toward accomplishment of
milestones and make recommendations to the BPN Project Team about allocation of
funding and resources within the network.

Dispute
Resolution:

Any disagreements that may arise in scientific or
programmatic matters (within the scope of the award) between award recipients
and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel
composed of three members will be convened. It will have three members: a
designee of the Steering Committee chosen without NIH staff voting, one NIH
designee, and a third designee with expertise in the relevant area who is
chosen by the other two; in the case of individual disagreement, the first
member may be chosen by the individual awardee. This special dispute resolution
procedure does not alter the awardee's right to appeal an adverse action that
is otherwise appealable in accordance with PHS regulation 42 CFR Part 50,
Subpart D and DHHS regulation 45 CFR Part 16.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and
405 of the Public Health Service Act as amended (42 USC 241 and 284) and under
Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.